The long-term goal of this application is to better understand how proliferation and growth at the mandibular condylar cartilage (MCC) is regulated and if it is different from growth in the primary cartilage (growth plate) of limbs. This understanding can be exploited to devise better treatment strategies for growth problems and persistent inflammatory disorders at the temporomandibular joint. Relatively little is known of how the molecular determinants of growth differ among cranial sutures, mandibular condylar cartilage, and the cranial base cartilages. Recent studies have provided clues that regulation of proliferation in the MCC may be more similar to that in cranial sutures than in limb cartilage. Accordingly, it is possible that proliferation and differentiation in MCC are regulated by mechanisms common to periosteum, not cartilage. We hypothesize that chondroprogenitor cells of the mandibular condylar cartilage and osteoprogenitor cells of cranial sutures share regulatory molecules and receptors, distinct from the proliferative chondrocytes of primary cartilage. This hypothesis will be tested by three specific aims: 1) In explant culture, establish localization of downstream mediators of Fgf-2 and Tgf-Beta2 activity (Twist and Dachl) in MCC, cranial suture (SUT), and the primary cartilage of the sphenooccipital synchondrosis (SOS). We will test the hypothesis that mediators of Fgf2 and Tgf-Beta2 activity are the same in MCC and SUT, and that they differ from mediators of Fgf2 and Tgf-Beta2 activity in SOS; 2) Establish whether removal of the periosteum from MCC, SUT, and SOS explants enhances or inhibits the expression of Twist or Dachl. We will test the hypothesis that the periosteum produces factors that modulate Twist and Dachl expression and activity differently in MCC, SUT, and SOS; 3) Test the findings of the explant studies in appropriate knockout mouse strains. We will test the hypothesis that reduction or elimination of specific mediators of Fgf2 or Tgf-Beta2 activity in vivo (Twist and Fgfr2HIc) has downstream consequences for MCC and SUT that are distinct from those in SOS. This information is critical, as most concepts of temporomandibular joint dysfunction (TMD) approach the TMJ as a synovial joint containing a typical articular cartilage. If the perichondrial cells in MCC share regulatory features with cells in SUT rather than in SOS, this assumption is not only erroneous but may lead to inappropriate treatment strategies.